Wolff 2017 Thesis
|Wolff C (2017) Impact of lipid metabolism on skeletal muscle mitochondrial function in type 2 diabetes mellitus patients. Dissertation p68.|
Abstract: Elevated plasma free fatty acids (FFA) may lead to ectopic lipid storage in skeletal muscle and liver, which is characteristic of type 2 diabetes mellitus (T2DM). Intramyocellular lipid content (IMCL) has been associated with insulin resistance, metabolic inflexibility and impaired mitochondrial oxidative capacity. Reduction of circulating FFAs by antilipolytic agents may therefore improve insulin sensitivity. However, the effect of alterations of circulating lipids on skeletal muscle mitochondrial function remains unclear.
The impact of FFAs on energy metabolism was examined in (i) a cross-sectional study, employing high-caloric meal ingestion in healthy, obese and T2DM patients, and in (ii) an interventional study, employing the antilipolytic agent Acipimox in T2DM patients. The cross-sectional study tested, whether ingestion of a high-caloric lipid-enriched meal would impair mitochondrial function, metabolic flexibility and insulin sensitivity, but increase IMCL. The interventional study tested, whether Acipimox would improve muscle mitochondrial oxidative capacity, metabolic flexibility, insulin sensitivity and IMCL in T2DM patients.
To allow for comparison, both studies applied identical methods. High-resolution respirometry allowed determining mitochondrial oxidative capacity ex vivo, while phosphorus magnetic resonance spectroscopy (31P-MRS) made it possible to assess mitochondrial function in vivo. Insulin sensitivity and metabolic flexibility were analyzed by hyperinsulinemic-euglycemic clamps along with indirect calorimetry measurements. Thiobarbituric acid reactive substances (TBARS) served as a measure for oxidative stress. IMCL and liver fat content were measured by proton MRS (1H-MRS), while IMCL was quantified histochemically in the interventional study.
The cross-sectional study revealed that glucose concentrations were higher in T2DM patients in comparison to obese participants and healthy controls before and after meal ingestion and circulating FFA were increased both in T2DM and in obese participants than in healthy lean humans. T2DM and obese humans had also lower whole body insulin sensitivity. Ex vivo mitochondrial oxidative capacity (state 3 respiration) was reduced in T2DM patients than in healthy participants. However, in vivo mitochondrial function, metabolic flexibility, TBARS and IMCL did not differ between groups. The interventional study showed that Acipimox decreased insulin sensitivity compared to control condition and placebo administration. Acipimox did neither affect mitochondrial density, mitochondrial oxidative capacity, IMCL content nor metabolic flexibility. Of note, plasma FFAs were increased upon Acipimox administration compared to both control and placebo conditions. Liver fat storage tended to be lower upon Acipimox compared to the control period, but not compared to the placebo period.
These studies showed that insulin resistance does not necessarily require impaired mitochondrial capacity and that circulating FFAs rather associate with insulin resistance than with abnormal mitochondrial function. In contrast to the initial hypothesis, even short-term Acipimox treatment increased circulating FFAs, likely due to the known ‘rebound’-effect, which masked any possible beneficial effect of preceding FFA lowering on muscle mitochondrial function, metabolic flexibility, insulin sensitivity and IMCL content. In conclusion, circulating FFAs have no major direct impact on muscle mitochondrial function and FFA-lowering by Acipimox fails to improve metabolic disturbances and cannot be recommended for treatment of T2DM patients.
Labels: MiParea: Respiration, Pharmacology;toxicology Pathology: Diabetes, Obesity
Organism: Human, Horse Tissue;cell: Skeletal muscle Preparation: Permeabilized tissue
Coupling state: LEAK, OXPHOS, ET Pathway: F, N, NS HRR: Oxygraph-2k